The present invention is generally in the area of methods for reconstruction of urothelial structures, especially bladders.
Traditionally, defects in the bladder and other urothelial structures have been corrected surgically. This has obvious disadvantages when there is a defect in the structure which requires closure of an opening for which there is insufficient tissue or when the structure itself is deformed or too small to meet the needs of the patient.
Bowel segments have been used in reconstruction of genitourinary structures in these circumstance. The use of bowel in genitourinary reconstruction is associated with a variety of complications, including metabolic abnormalities, infection, perforation, urolithiasis, increased mucus production and malignancy, as reviewed by Atala, A. and Retik, A.: Pediatric urology—future perspectives. In: Clinical Urology. Edited by R/J. Krane, M. B. Siroky and J. M. Fitzpatrick. (Philadelphia: J. B. Lippincott, 1993). Alternative approaches need to be developed to overcome the problems associated with the incorporation of intestinal segments into the urinary tract. Natural tissues and synthetic materials that have been tried previously in experimental and clinical settings include omentum, peritoneum, seromuscular grafts, de-epithelialized segments of bowel, polyvinyl sponge and polytetrafluoroethylene (Teflon). These attempts have usually failed.
It is evident that urothelial-to-urothelial anastomoses are preferable functionally. However, the limited amount of autologous urothelial tissue for reconstruction generally precludes this option. In cell transplantation, donor tissue is dissociated into individual cells or small tissue fragments and either implanted directly into the autologous host or attached to a support matrix, expanded in culture and reimplanted after expansion. Autologous skin cells have been used in this fashion in the treatment of extensive burn wounds, as reported by Green, et al., “Growth of cultured human epidermal cells into multiple epithelia suitable for grafting”, Proc. Natl. Acad. Sci., 76:5665 (1979); O'Connor, et al., “Grafting of burns with culture epithelium prepared from autologous epidermal cells”, Lancet, 1:75 (1981); and Burke, et al., “Successful use of a physiologically acceptable artificial skin in the treatment of an extensive burn injury”, Ann. Surg., 194:413 (1981).
A suitable material for a cell transplantation matrix must be biocompatible to preclude migration and immunological complications, and should be able to support extensive cell growth and differentiated cell function. It must also be resorbable, allowing for a completely natural tissue replacement. The matrix should be configurable into a variety of shapes and should have sufficient strength to prevent collapse upon implantation. Recent studies indicate that the biodegradable polyester polymers made of polyglycolic acid seem to fulfill all of these criteria, as described by Vacanti, et al., “Selective cell transplantation using bioabsorbable artificial polymers as matrices”, J. Ped. Surg., 23:3 (1988); Cima, et al., “Hepatocyte culture on biodegradable polymeric substrates”, Biotechnol. Bioeng., 38:145 (1991); Vacanti, et al., “Synthetic polymers seeded with chondrocytes provide a template for new cartilage formation”, J. Plast. Reconstr. Surg., 88:753 (1991).
The feasibility of using biodegradable polymers as delivery vehicles for urothelial cell transplantation has been demonstrated by studies showing that urothelial cells will adhere to synthetic polymers composed of polyglycolic acid and survive in vivo, as reported by Atala, et al., “Formation of urothelial structures in vivo from dissociated cells attached to biodegradable polymer scaffolds in viva”, J. Urol., part 1, 148:658 (1992).
For implantation of cells on polymer matrices to be successful in patients, a source of an effective concentration of cells has to be available, and the urothelial cell population has to survive for extended times on implanted polymers and proliferate extensively in vivo. Most importantly, implanted cells have to remain intact as defined structures as the polymer implant degrades over time under physiological conditions. Polymer scaffolds would have to include bladder smooth muscle in concert with urothelial cells to reconstitute a functional bladder wall.
An easier solution would be to develop a method for correcting defects which did not require obtaining and implanting cells on the polymer matrices. However, initial studies with chondrocytes implanted in tissue in the absence of a matrix and implantation of polymer alone has not been demonstrated to result in appropriate ingrowth and proliferation of cells.
It is therefore an object of the present invention to provide a method and means for reconstructing defects in organ structures, especially urothelial structures such as the bladder, ureter and urethra, which does not require exogenous cells.